In this project we seek to advance understanding of the endocrine mechanisms of stress and of the role of corticotropin releasing hormone (CRH) in normal and stress physiology and in disorders of hypothalamic-pituitary-adrenal function. Rapid progress in this area has been made prossible by the recent discovery of the chemical structures of, first, ovine CRH (oCRH) and, more recently, of human CRH (hCRH). Our objectives have been to determine the dose-response relationships for ovine and human CRH in nonhuman primates and in man, to study the metabolic clearance rates of these peptides, to develop methods to measure CRH accurately in tissues and in biological fluids of patients with abnormalities of the hypothalamic-pituitary-adrenal axis, to develop a clinical CRH test, and to evaluate its usefulness in adrenal insufficiency, Cushing's syndrome, and pseudo-Cushing's states. Our studies to date have shown that both ovine and human CRH are active in non-human primates and man. The appropriate dose and mode of testing man have been established and the pharmacological parameters have been determined in both primates and men. CRH stimulation appears to be a useful test in the differential diagnoisis of adrenal insufficiency, Cushing's syndrome and pseudo-Cushing's states. Physiological experiments suggest that Cushing's disease is pituitary, whereas hypercortisolism in depression is hypothalamic in orgin. Succuessful treatment of Cushing's disease with surgery is followed by normalization of the CRH stimulation test. Human CRH causes brief plasma ACTH and cortisol elevations in human subjects that are pulselike and mimic the spontaneously occurring physiologic ACTH and cortisol secretory episodes. This is explained by the brief plasma half-life and the high MCR of this peptide. These properties of hCRH make it an important means for the study of the physiology of the hypothalamic-pituitary-adreanl axis. Administration of hCRH in a pulsatile fashion restores the secretory pattern of cortisol in patients with hypothalamic adrenal insufficiency.